The basic helix-loop-helix tal-1 gene plays a key role in hematopoiesis, and its expression is tightly controlled through alternative promoters and complex interactions of cis-acting regulatory elements. tal-1 is not expressed in normal T cells, but its transcription is constitutive in a large proportion of human T cell leukemias. We have previously described a downstream initiation of tal-1 transcription specifically associated with a subset of T cell leukemias that leads to the production of NH(2)-truncated TAL-1 proteins. In this study, we characterize the human promoter (promoter IV), embedded within a GC-rich region in exon IV, responsible for this transcriptional activity. The restriction of promoter IV usage is assured by a novel silencer element in the 3′-untranslated region of the human gene that represses its activity in erythroid but not in T cells. The silencer activity is mediated through binding of a tissue-specific nuclear factor to a novel protein recognition motif (designated tal-RE) in the silencer. Mutation of a single residue within the tal-RE abolishes both specific protein binding and silencing activity. Altogether, our results demonstrate that the tal-1 promoter IV is actively repressed in cells of the erythro-megakaryocytic lineage and that this repression is released in leukemic T cells, resulting in the expression of the tal-1 truncated transcript.
Erythroid-specific inhibition of the tal-1 intragenic promoter is due to binding of a repressor to a novel silencer
Courtes, C.; Lecointe, N.; Le Cam, L.; Baudoin, F.; Sardet, C.; Mathieu-Mahul, D.
J Biol Chem
2000-01-14 / vol 275 / pages 949-58
Humans; Animals; Mice; Molecular Sequence Data; Repressor Proteins; Base Sequence; Cell Line; *Gene Silencing; Binding Sites; T-Lymphocytes/metabolism; Sequence Alignment; Exons; Sequence Homology, Nucleic Acid; Hela Cells; 3T3 Cells; *Promoter Regions (Genetics); Consensus Sequence; K562 Cells; *Proto-Oncogene Proteins; Basic Helix-Loop-Helix Transcription Factors; Helix-Loop-Helix Motifs; *Transcription Factors; 5' Untranslated Regions/genetics; DNA-Binding Proteins/*genetics/metabolism; Endothelium, Vascular/cytology/metabolism; Leukemia, T-Cell/genetics; Megakaryocytes/*metabolism; Regulatory Sequences, Nucleic Acid